Researchers Identify Key Genetic Trigger Of Acute Myeloid Leukemia

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Acute Myeloid Leukemia

A gene called N-Myc leads a double life in certain white blood cells when it is overexpressed, helping to trigger acute myeloid leukemia (AML) under some conditions while triggering apoptosis, or cell suicide, under other conditions, according to results of a mouse study done by investigators at St. Jude Children's Research Hospital.

"Since N-Myc overexpression frequently occurs in human AML as well, this discovery gives researchers an important insight into N-Myc's role in human AML," said Gerard Grosveld, Ph.D., chair of the St. Jude Department of Genetics and Tumor Cell Biology. "It also might contribute to new strategies for treating this leukemia or disrupting this gene's ability to cause it." Grosveld is senior author of a report on this work that appearsin the Nov. 15 issue of "Cancer Research."

The researchers showed that artificially forcing overexpression of N-Myc in bone marrow cells of mice strongly promotes AML; and that levels of N-Myc RNA (the decoded form of a gene) from 137 patients with AML were between two- and 33-fold higher than in normal bone marrow cells.

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The team also showed that myeloid cells that were genetically engineered to overexpress N-Myc became immortalized, or had an unlimited life span, and that this was associated with changes in levels of certain proteins known to occur when human myeloid cells become leukemic.

The St. Jude team demonstrated in cell cultures that N-Myc can also trigger apoptosis and kill the cell instead of making it reproduce uncontrollably. Specifically, most myeloid cells over-expressing N-Myc died within 24 hours when they were deprived of an anti-apotosis, growth-promoting protein called IL-3. In addition, there was a significant decrease in the activity of several other proteins that normally cooperate to prevent apoptosis -- a known effect of the protein made by N-Myc, Grosveld said.

The researchers then showed that mice that received bone marrow cells that were genetically engineered to overexpress N-Myc developed AML and died within 50 days.

Finally, Grosveld's team showed that the transformation of a myeloid cell to a leukemic cell requires overexpression of Twist, a gene that normally inhibits apoptosis.

"This work demonstrates the critical role N-Myc plays in Acute Myeloid Leukemia and maps out the cooperation with other genes that blunt N-Myc's apoptotic effects, thereby tipping the delicate balance between cell death and cancer," Grosveld said.

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